tbuckley/cabot-search huggingface dataset:
P15.09.B ALONG-TRACT ANALYSIS OF DTI PARAMETERS TO DETECT EXTENSION AND DIRECTION OF WHITE MATTER ABNORMALITIES IN PATIENTS WITH DIFFUSE LOW GRADE DIFFUSE GLIOMAS
Authors: M Fahlström, S Mirza, F Latini
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse Low-grade gliomas (DLGG) show extensive infiltration through white matter (WM) tracts. Diffusion tensor tractography with along-tract analysis (ATA) has been used to non-invasively assess the microstructural integrity of WM pathways. The possibility to detect the extension and direction of WM infiltration using local DTI-based parameters in DLGG has been investigated with different techniques but displayed inconsistent results. The aim of this study was to use ATA analysis to compare DTI parameters in white matter pathways invaded/spared by DLGGs. MATERIAL AND METHODS Fourteen patients with a diagnosis of DLGG were included. DLGGs were manually segmented based on 3D-FLAIR images spatially normalised to MNI space. DTI was acquired for all the subjects using a single-shot echo-planar sequence on a 3T with 48 sampling directions. DTI data was reconstructed within MNI space using q-space diffeomorphic reconstruction (QSDR) in DSI studio. Five bilateral sets of WM pathways were reconstructed based on the HCP-1021 template. ATA was performed for FA, AD and RD for all five bilateral WM pathways. In short, all WH pathways were stretched to the same length of 100 indices, FA, RD and AD were sampled for each index. An overlay of tumour 3D reconstruction was used to detect contact with WM pathways . Not affected WM pathways were considered normal and included as normal data. All WM pathways were compared individually and per index to the normal data using a z-test. RESULTS Eight patients had an IDH-mutated grade 2 astrocytoma, 6 had a 1p19q co-deleted grade 2 Oligodendroglioma. ATA analysis displayed a clear difference between invaded and non-invaded WM pathways in all the DTI parameters. In infiltrated pathways, the z-test displayed: 1) significant lower FA only within a limited tumoral area but not along the all infiltrated segment; 2) RD was significantly higher compared with normal data in a larger area even beyond the tumour borders; 3) AD was significant lower in the infiltrated WM pathways beyond the tumour borders. CONCLUSION s: ATA analysis is a sensitive and reliable method to detect the extension and the direction of diffusion abnormalities within and beyond the DLGG extension. Our results support other studies suggesting that FA is not an enough sensitive index to detect gliomas related WM abnormalities. A wider use of this method may be valuable to better plan the surgical resection of patients with DLGG or to tailor radiotherapy planning according to WM invasion.
P02.21.A A BIOBANK OF IDH1-MUTANT CELL LINES FOR STUDYING TUMOR HETEROGENEITY, PROGRESSION AND TARGET IDENTIFICATION
Authors: L Garcia, D Pineau, S Hideg, V Rigau, A Darlix, L Bauchet, H Duffau, J Hugnot
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse low grade gliomas are grade II brain tumors mainly affecting young patients. Most of these tumors have a mutation in the IDH1 gene (isocitrate dehydrogenase 1) gene causing differentiation defects and cell accumulation in the brain. These tumors are classified as astrocytomas or oligodendrogliomas and often progress into high grade gliomas (i.e IDH1-mutant grade IV astrocytomas and grade III oligodendrogliomas). We and others have shown that IDH1-mutant diffuse low grade gliomas contain 3 types of tumoral cells, resembling astrocytes, oligodendrocytes and neural progenitors, the formation of which is regulated by Notch signaling (Augustus et al, 2021, Cells, Suvà et al, 2020, Cancer Cell). There is a significant lack of cellular tools to study these tumors in vitro, hindering the development of new therapies. We aimed to address this by creating a fully annotated biobank of IDH1-mutant cell lines derived from different grades of tumors and carrying various rare mutations. MATERIAL AND METHODS We derived and collected 8 IDH1-mutant cell lines (4 astrocytomas grade II/III/IV and 4 grade III oligodendrogliomas). These cell lines were characterized using bulk RNA sequencing under different culture conditions, single-cell RNA sequencing to determine their cellular heterogeneity, and immunofluorescence and western blotting. RESULTS Our findings show that these IDH1-mutant cell lines exhibit different growth rates and morphologies and are phenotypically related to brain radial glial cells, oligodendrocyte progenitor cells, or more mature oligodendrocytes. Some of these cell lines are multipotent and contain astrocyte-like and oligodendrocyte-like cells. Our current work aims to purify different cell subpopulations to study their properties and plasticity. Additionally, we are analyzing pathways and differentially expressed genes involved in IDH1-mutant cell quiescence and malignant progression. CONCLUSION In summary, we present a novel and deeply-annotated biobank of 8 IDH1-mutant cell lines derived from different grades of gliomas, providing an invaluable resource to study the cellular and molecular heterogeneity of IDH1-mutant gliomas, their progression to high-grade gliomas, and the identification of new therapeutic targets. We anticipate that our biobank may facilitate the development of personalized medicine for patients with IDH1-mutant gliomas and accelerate the discovery of new therapeutic strategies.
P17.07.A REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: AN ITALIAN OBSERVATIONAL, MULTICENTRIC AND PROSPECTIVE TRIAL (REGOMA-OSS)
Authors: M Caccese, M Padovan, I Desideri, V Villani, M Simonelli, M Buglione, S Chiesa, E Franceschi, P Gaviani, I Stasi, C Caserta, S Brugnara, I Lolli, E Bennicelli, P Bini, A Cuccu, G Cerretti, G De Salvo, G Lombardi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In the randomized phase 2 REGOMA trial, regorafenib has shown promising activity in recurrent glioblastoma patients with a significantly longer survival compared to the standard lomustine therapy. Subsequently, in Italy regorafenib was approved as second-line therapy by the Italian Medicines Agency. We performed a large multicenter, prospective and observational study to confirm REGOMA data in the real-world setting. METHODS Based on the REGOMA results, at least 150 patients had to be enrolled to estimate a 1-year survival rate with a precision of 7.8% and a confidence interval of 95%. Major inclusion criteria were: histologically confirmed diagnosis of glioblastoma according to WHO 2016, radiologically documented first relapse/progression after Stupp treatment, good performance status (ECOG PS 0-1), adequate hepatic and hematological function, stable or decreasing corticosteroid use within 7 days before starting regorafenib.Regorafenib has been administered at the standard dose of 160 mg/die for 3 weeks on/1 week off, until disease progression or unacceptable toxicity. Brain MRI has been performed within 14 days before starting regorafenib and then every 8-12 weeks. Primary endpoint is overall survival. Secondary endpoints include: progression-free survival, objective response rate, toxicity and quality of life. RANO criteria is used for response evaluation, CTCAE v. 5.0 for adverse events, EORTC QLQ-C30 and brain module BN20 for quality of life. Recruitment started in September 2020 and finished in October 2022. 191 recurrent glioblastoma patients were prospectively enrolled from 29 cancer centers in Italy: median age was 59 years (IQR 52.6-66.9), 68% male and 32% female, ECOG PS was 0 in 84 (44%), 115 pts (60%) undertook steroids at baseline. MGMT was methylated in 43% and IDH1/2 was wild-type in 92% of patients. The results from this large multicenter Italian study are expected in the second half of 2023.
P18.01.A A MORPHOMETRIC ANALYSIS OF 40 DRY ASIAN SKULLS TO INVESTIGATE ANATOMICAL VARIABILITY IN THE SUPRASELLAR REGION AND ITS IMPLICATIONS IN MENINGIOMA SURGERY
Authors: J Geldart
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Meningiomas are the most common type of primary brain tumour and when symptomatic, are usually treated by surgical resection. Removing skull-base meningiomas is challenging and subtotal resection remains common, despite utilising the latest surgical METHODS . In the suprasellar region, surgery is particularly high risk and carries a 10-20% rate of postoperative visual impairment. This morphometric analysis of 40 dry skulls furthers our understanding of anatomical variability of 3 structures in the suprasellar region: the limbus sphenoidale (LS), prechiasmatic sulcus (PS) and optic strut (OS). Understanding suprasellar anatomical variability is vital for neurosurgeons operating within the region to reduce complication rates and in achieving gross total resection. METHODS Variants of the LS (A, B and C) are defined according to descriptions used from a previous study. Curved and straight lengths of the LS are measured using metal callipers and string. Between the three variants, statistical analysis is used to compare differences in lengths, and the ratio between their curved and straight length. PS angle, length and width are measured according to previous studies’ definitions. OS position is determined by measuring its distance from the LS and a drawn midline. Skulls are grouped using PS variables and OS position according to adapted classification systems used in previous studies. RESULTS Variants A, B and C of the LS exhibited incidences of 33.33%, 52.82% and 15.39%, respectively. Limbus ratio was significantly different (p&amp;lt;0.05) between variants. Average sulcal angle was 32 ± 13.3°, whilst sulcal type ranked in prevalence: narrow flat sulci (34.21%)&amp;gt; very narrow steep (28.95%)&amp;gt; very narrow flat (21.05%) &amp;gt; narrow steep (15.79%). 32.50% and 18.42% of struts exhibited notable differences in their distances from the midline and from the LS, respectively. CONCLUSION The present study improves our understanding of the prevalence of anatomical variants within the suprasellar region and has implications for meningioma surgery. The type C variant is an overhanging ridge, underneath which meningiomas could be hidden from a surgeon’s view during transcranial procedures. Only two studies have previously documented the type C variant, whose incidence in the present study (15.39%) is within the boundaries of previous research; patients with this variant might require removal of the landmark during surgery to achieve gross total resection. The PS displayed varying degrees of steepness, and skulls were on average steeper than previously documented populations. A considerable proportion of skulls exhibited notable differences in left and right OS position. Establishing PS morphology and OS position preoperatively might be helpful in reducing the risk of visual impairment in future operations through better understanding the course of the optic nerve.
P03.08.A HIGH-DIMENSIONAL CHARACTERISATION OF THE CELLULAR AND MOLECULAR CHANGES IN THE HUMAN BRAIN AFTER RADIOTHERAPY
Authors: T O Millner, P Panday, N Pomella, S Badodi, S Marino
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In the UK ~40,000 intrinsic and metastatic brain tumours are diagnosed each year. Although targeted radiotherapy (RT) is integral to increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT treatment epigenetic changes occur in the neoplastic tissue, but few studies have assessed these in non-neoplastic brain tissue and results are highly variable. MATERIAL AND METHODS To explore the effects of RT on patient-specific methylation, we retrospectively identified 19 samples, mainly metastatic tumours, that had undergone stereotactic-RT followed by resection, and contained peri-lesional brain tissue, as well as 14 controls. Peri-lesional brain was micro-dissected, followed by DNA methylation profiling and RNA-sequencing. RESULTS Clustering of DNA methylation data showed distinct patterns between the two groups, whilst RNA-seq revealed 1,887 differentially expressed genes. Pathway analysis with GSEA identified differentially represented pathways, including: innate immune system, trans-synaptic signalling, olfactory signalling, regulation of supramolecular fibre organisation, and pattern specification. Computational deconvolution of cellular composition showed increased activated dendritic cells and B-cells, and reduced smooth muscle cells and several sub-sets of astrocytes in the RT samples. CONCLUSION We are currently further investigating these findings using spatial transcriptomics and proteomics to produce the first high-dimensional characterisation of the irradiated human brain. This will also provide the first direct evidence of epigenetic dysregulation after targeted-RT, and assess novel epigenetically-regulated genes, which will be validated with single cell tissue-based imaging techniques. A range of epigenetic-based drugs are undergoing clinical trials and we aim to identify targets for radiomitigation in brain tumour patients.
P11.06.B PERFUSION MRI IMPACTS MANAGEMENT IN PATIENTS WITH TREATED GLIOMA: FIRST RESULTS FROM THE PERISCOPE PROJECT
Authors: W Teunissen, S Derks, J Labrecque, C Lam, M Hunink, L Dirven, A van der Hoorn, M Smits
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Perfusion MRI (pMRI) is widely used for differentiation between progressive disease and pseudoprogression in patients with treated glioma. Although pMRI has long been available, its clinical relevance and utilization are not well known. We investigate the role of pMRI in clinical management decisions and its association with overall survival (OS) in patients with glioma under surveillance after focal radiotherapy. MATERIALS AND METHODS We performed a retrospective multicenter cohort study of patients treated for glioma between 2008 and 2021. At the moment of first substantial abnormalities on follow-up MRI, both with or without pMRI, we collected the management decisions, information about the (p)MRI and clinical parameters from the patient records. Causal inference methods were used to design a model predicting the probability of a management change with or without pMRI at first scan after radiotherapy (baseline), during chemotherapy (on-treatment) and after treatment. A multivariable Cox-proportional hazards model was used for OS analysis (adjusted for age, clinical performance, surgery type, histopathological diagnosis). Subgroup analyses were performed for patients with glioblastoma only. RESULTS 976 patients (mean age 57.2 ±12.4 years; 649 men) were included in 7 neuro-oncological referral centers (4 academic), 548 with and 428 without pMRI. Eighty percent of pMRI scans were of sufficient quality. Eighty percent of patients had glioblastoma and in this group, during the “on-treatment” phase, there was a 16% lower probability of change in clinical management in patients with pMRI, which was more pronounced (37%) in academic hospitals. OS was longer in patients with versus without pMRI with a hazard ratio of 0.77 (95%CI: 0.67,0.89, p&amp;lt;0.001). These findings were similar when only considering patients with glioblastoma. CONCLUSION pMRI was associated with fewer management changes while patients were on treatment, and with longer OS. This latter result must be interpreted with caution due to possible confounding.:
P16.01.A THE CASE OF AGGRESSIVE DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN ADULT TREATED WITH CRANIOSPINAL IRRADIATION AND TEMOZOLOMIDE
Authors: J Hwang, C Lee, S Yoon, M Kim, K Park, S Park
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare tumor, which was introduced as a separate entity in the 2016 World Health Organization classification of central nervous system tumors. It is most common in pediatric age, but very rare in adults. Literature demonstrates limited reports regarding treatment strategy in adult. We present a case of young female affected by DLGNT with aggressive behavior. MATERIAL AND METHODS A 28-year-old woman presented with severe headache and vomiting. Brain MRI showed diffuse leptomeningeal enhancement with hydrocephalus. At first, she was under suspicion of tuberculosis meningitis with mild increased protein level in CSF study. Her symptom rapidly improved after ventriculoperitoneal shunt and she started anti-tuberculosis medication. Despite 8-month of medication, her neurological status gradually deteriorated with paraparesis and follow-up MR images showed progression of disease. She underwent open biopsy of superficial brain lesions. RESULTS Intraoperatively, multiple nodular masses were attached inner side of dura mater and diffuse adhesion on subarachnoid space of brain surface. Histological examination revealed small round cells with oligodendroglial-like aspects. Immunohistochemistry showed positivity for Olig2, synaptophysin and S100. Chromosome 1p deletion was confirmed by FISH. Next-generation sequencing profile disclosed mutation of H3K28M, FGFR1 and ATRX. Diagnosis was consistent with DLGNT. She received craniospinal irradiation of 36 Gy in 20 fractions, then started chemotherapy with temozolomide (TMZ) at a dose 200mg/m2/day for 5 days in 4 weeks. After 4 cycles of TMZ, MR images demonstrated stable disease. CONCLUSION DLGNT is a very rare tumor in adult. Diagnosis needed high level of suspicion and histological confirmation. We present a very rare adult DLGNT patient with aggressive clinical features who showed stable state treated with craniospinal irradiation and TMZ chemotherapy.
P11.80.A DOUBLE BLIND RANDOMISED TRIAL WITH ADD-ON OF VALGANCICLOVIR OR PLACEBO TO STANDARD THERAPY OF NEWLY DIAGNOSED GLIOBLASTOMA
Authors: G Stragliotto, M Pantalone, P Brandas, L Sagerup-Bjorland, C Söderberg-Naucler
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The origin of glioblastoma is not known. Our earlier and other groups research have shown the presence of cytomegalovirus in glioblastoma, but not in adjacent tumor-free tissue. Furthermore there is a significant correlation between the amount of virus proteins in the tumor and prognosis, patients with low tumoral load have longer survival compared to patient with hogh tumoral viral load. In a retrospective study with 100 newly diagnosed patients with glioblastoma we showed tha the addition of valganciclovir yielded a median survival of 25 months as compared to 13 months for contemporary controls from the same institution. In the case of maximal surgical resection, the median survival reached 29 months. We therefore aimed to run a randomised doule blind study in newly diagnosed glioblastoma. MATERIAL AND METHODS The study started in September 2019, and has the goal to recruit 220 patients, 110 in the valganciclovir group and 110 in the placebo. A macroscopic surgery (at least 90% resection of contrast enhancing tumor on post op MRI), followed by radiation and chemotherapy with temozolomide. Patients receive the study drug, 900mg twice daily during the first 6 weeks, followed by maintenance 450mg twice daily for 2 years. There is no cross-over. The use of Optune is allowed. There is a stratification for MGMT methylation status. Only IDH1 wt tumors can be included, and the randomization has to take place within 10 weeks from surgery. The primary outcome is overall survival, secondary endpoints are the proportion surviving at 2 years and quality of life. 20 patients who fullfilled inclusions criteria have not been randomised. RESULTS since September 2019, 120 patients have been included at Karolinska Hospital in Stockholm. The oncology clinics in Oslo and Stavanger started including patients in September 2022, and have so far included 20 patients. At Karolinska there are 47 MGMT methylated and 73 unmethylated. Nineteen deceased patients and 45 deceased respectively. The median survival is 22 and 14 months respectively. Forteen patients with MGMT methyl completed the study (24 months and 6 months follow-up) versus 8 in the unmethylated. The survival of 20 patients not randomised was 18 months. Five patients showed reversibel hematological side effects grade 3-4, always with the initial high dose and concomittant to radiochemotherapy. No patient stopped the study due to side effects. CONCLUSION the is an ongoing trial, that has recruited about 35 patients per year at the main center, even during the 2 years of pandemics. about half of newly diagnosed patients are eligible for this study, and more than 80% of eligible patients are randomized which is remarkable for this category of patients. There may be a trend as a group for positive survival results, but we need to wait the final results, which may be available in 2-3 years. The study wil recruit until December 2024.
P16.07.B PROSPECTIVE DOUBLE ARM PHASE 2 RANDOMIZED TRIAL FOR PATIENTS WITH MULTIPLE BRAIN METASTASIS AND/OR LEPTOMENINGEAL CARCINOMATOSIS: COMPARISON OF WHOLE BRAIN RADIATION THERAPY (WBRT) ALONE AND WBRT PLUS SILIBININ
Authors: E Clerici, P Navarria, L Bellu, B Marini, F Lobefalo, M Scorsetti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Occurrence of brain metastases (BMs) is increasing given availability of Magnetic Resonance Imaging (MRI) able to detect also small brain lesions, and most effective systemic therapy able to better control extra-cranial disease. Estimated 20% of patients with cancer will develop BMs. In case of limited brain metastases, radiosurgery or hypofractionated radiosurgery is treatment of choice. A subgroup of patients characterized by extensive brain disease and/or leptomeningeal carcinomatosis can require whole brain radiotherapy (WBRT). Since the 1950s, WBRT has been the most treatment used for patients with multiple BMs, given its effectiveness in palliation, widespread availability, and ease to deliver. However, the median overall survival (OS) recorded is restricted to 3 months, on the average. A better understanding of molecular and cellular mechanisms underlying brain metastasis might be expected to lead of improvements in overall survival. Recent studies demonstrated that active signal transducer and activator of transcription 3 (STAT3) in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis, even at advanced stages of colonization. Silibinin is a natural polyphenolic flavonoid isolated from seed extracts of herb milk thistle. It has been shown to impair STAT3 activation, and in preclinical studies, show an anticancer effects in vitro and in vivo. Based on this background, we designed a double arm phase 2 randomized trial evaluating the benefit of Silibinin associated to WBRT respect to WBRT alone. Primary endpoint is OS, secondary endpoints are toxicity in term of corticosteroid therapy use, brain failure (BF) and progression free survival (PFS). MATERIAL AND METHODS Forty-four patients will be enrolled in two years. Patients with histological or cytological confirmation of solid tumor malignancy, clinical indication for WBRT and Karnofsky performance status (KPS) ≥60 will be enrolled. In arm A experimental, WBRT is concomitant to Silibinin, in arm B control, WBRT alone will be administered. In both arms, total dose of radiotherapy is 30 Gy in 10 fractions. Quality of life and use of corticosteroids will be evaluated first, last day of RT, and during follow-up. Outcome will be evaluated by MRI or CT at 2 months after RT, and every 3 months thereafter. RESULTS From March 2023, 6 patients were enrolled, 2 patients in Arm A and 4 in arm B. Primary histology was breast cancer in 3 patients and non small cell lung cancer in 3. In arm A, 1 patients dismissed RT for worsening of general conditions related to rapid lung progression. CONCLUSION WBRT with or without Silibinin was well tolerated, no acute toxicities or increase of corticosteroids were observed.